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Promotion of Plasmalogen Biosynthesis Reverse Lipid Changes in a Barth Syndrome Cell Model T ⁎ José Carlos Bozelli Jr.A, Daniel Lub, G

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Promotion of Plasmalogen Biosynthesis Reverse Lipid Changes in a Barth Syndrome Cell Model T ⁎ José Carlos Bozelli Jr.A, Daniel Lub, G BBA - Molecular and Cell Biology of Lipids 1865 (2020) 158677 Contents lists available at ScienceDirect BBA - Molecular and Cell Biology of Lipids journal homepage: www.elsevier.com/locate/bbalip Promotion of plasmalogen biosynthesis reverse lipid changes in a Barth Syndrome cell model T ⁎ José Carlos Bozelli Jr.a, Daniel Lub, G. Ekin Atilla-Gokcumenb, Richard M. Epanda, a Department of Biochemistry and Biomedical Sciences, McMaster University, Health Sciences Centre, Hamilton, Ontario L8S 4K1, Canada b Department of Chemistry, University of Buffalo, The State University of New York, Buffalo, NY 14260, USA ARTICLE INFO ABSTRACT Keywords: In Barth syndrome (BTHS) mutations in tafazzin leads to changes in both the quantities and the molecular Barth syndrome species of cardiolipin (CL), which are the hallmarks of BTHS. Contrary to the well-established alterations in CL Plasmalogen associated with BTHS; recently a marked decrease in the plasmalogen levels in Barth specimens has been Cardiolipin identified. To restore the plasmalogen levels, the present study reports the effect of promotion of plasmalogen Phospholipidomics biosynthesis on the lipidome of lymphoblasts derived from Barth patients as well as on cell viability, mi- Mass spectrometry tochondria biogenesis, and mitochondrial membrane potential. High resolution 31P NMR phospholipidomic Mitochondrial properties analysis showed an increase in the levels of plasmenylethanolamine (the major plasmalogen in lymphoblasts), which reached values comparable to the control and a compensatory decrease in the levels of its diacyl-PE counterpart. Importantly, 31P NMR showed a significant increase in the levels of CL, while not altering the levels of monolysocardiolipin. Mass spectrometry measurements showed that the promotion of plasmalogen bio- synthesis did not change the molecular species profile of targeted phospholipids. In addition, promotion of plasmalogen biosynthesis did not impact on cellular viability, although it significantly decrease mitochondria copy number and restored mitochondrial membrane potential. Overall, the results showed the efficacy of the promotion of plasmalogen biosynthesis on increasing the CL levels in a BTHS cell model and highlight the potential beneficial effect of a diet supplemented with plasmalogen precursors to BTHS patients. 1. Introduction peripheral membrane, instead of parallel cristae that often extend across the entire organelle observed in controls [9]. In addition, CL also Barth Syndrome (BTHS) is an X-linked recessive disease caused by plays a role in keeping the integrity of the inner mitochondrial mem- mutations in the gene that encodes tafazzin [1,2]. Tafazzin is a lyso- brane (IMM) and alterations that compromise it would result in dis- phospholipid-phospholipid transacylase involved in the last step of sipation of the proton gradient that drives ADP phosphorylation. In- cardiolipin (CL) biosynthesis [3,4]. In BTHS loss-of-function of tafazzin deed, BTHS mitochondria exhibit increased proton leakage, decreased leads to a lower content of CL as well as more heterogeneous molecular membrane potential, and a decreased respiratory coupling index species of this lipid and accumulation of monolysocardiolipin (MLCL), [9–12]. Moreover, in Barth specimens, changes in CL lead to destabi- which are considered the hallmark of BTHS [5–7]. In eukaryotes, CL is a lization of mitochondrial super complexes (SC) [9,13,14]. Likewise, mitochondria-specific lipid, which has been reported to play crucial assembly of mitochondrial SC induces CL remodeling and, as a con- roles in the structure and function of mitochondria [8]. Hence, it is not sequence, its stabilization [15]. Mitochondria are key players in cellular unexpected that a major focus of research in this disease has been to redox metabolism and disruption of mitochondrial SC is known to result understand the molecular events resulting from changes in both the in increased production of reactive oxygen species (ROS) [16,17]. In- quantities and the molecular species of CL on mitochondrial structure deed, in several BTHS specimens elevated ROS production has been and function. reported [9,12,18,19]. Cells from BTHS patients usually display in- In BTHS mitochondrial morphology is aberrant, presenting swollen creased mitochondria biogenesis as indicated by the rise in the AMP/ and enlarged mitochondria with malformed cristae structures, which ATP ratio and mitochondria copy number when compared to controls, have lower surface area and appear round and disconnected from the which is proposed to occur for cellular compensation due to the ⁎ Corresponding author at: Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada. E-mail address: [email protected] (R.M. Epand). https://doi.org/10.1016/j.bbalip.2020.158677 Received 20 November 2019; Received in revised form 6 February 2020; Accepted 27 February 2020 Available online 29 February 2020 1388-1981/ © 2020 Elsevier B.V. All rights reserved. J.C. Bozelli, et al. BBA - Molecular and Cell Biology of Lipids 1865 (2020) 158677 impaired mitochondria [9,11]. the efficacy of the promotion of plasmalogen biosynthesis on increasing While the alterations in CL associated with BTHS are well-estab- the CL levels in a BTHS cell model and suggest that a diet supplemented lished, currently there has been an increased awareness of more with plasmalogen precursors could be beneficial for BTHS patients. widespread changes in the lipid composition of cells depleted of ta- fazzin function. Of note, it is the recent identification of a decrease in the plasmalogen levels in organs obtained from tafazzin knockdown 2. Materials and methods mice as well as blood cells derived from BTHS patients, which clearly indicate that plasmalogen loss is associated with BTHS [20,21]. 2.1. Materials Plasmalogens are members of a subclass of glycerophospholipids, which differ from their diacylglycerophospholipid counterpart by Sodium dodecyl sulfate (SDS) was from Bioshop (Canada). 2-etha- having a fatty alcohol linked via a vinyl-ether bond at the sn-1 position nesulfonic acid (MES), ethanolamine, CsOH, butylated hydroxytoluene of the glycerol moiety rather than an esterified fatty acid. Plasmalogens (BHT), ethylenedinitrilo-tetraacetic acid (EDTA), bovine serum albumin fl comprise up to 20% of the total phospholipid mass in humans and are (BSA), carbonyl cyanide p-(tri uoromethoxy)phenyl-hydrazone constituents of the plasma membrane as well as intracellular mem- (FCCP), methanol (HPLC grade), and chloroform (HPLC grade) were branes (nucleus, endoplasmic reticulum, post-Golgi network, mi- from Sigma-Aldrich (St. Louis, MO). D2O (99.9 atom %D) was from tochondria) [22]. Plasmenylethanolamine (PE-Pls) is the predominant Cambridge Isotope Laboratories (Tewksbury, MA). Roswell Park plasmalogen found in most of human cells, except in cardiac and ske- Memorial Institute (RPMI) 1640 Medium was from Gibco letal muscles and mature spermatozoa where high proportions of both (Gaithersburg, MD). Fetal bovine serum (FBS) was from Wisent PE-Pls and plasmenylcholine are found [22]. Although the physiolo- (Canada). 1-O-hexadecyl-sn-glycerol (HG) was from Avanti Polar Lipids gical role of plasmalogen remains elusive, several studies had shed light (Alabaster, AL). All reagents were used as received. on some of their physical, chemical, and biological functions. For in- stance, it has been reported that the vinyl-ether bond at the sn-1 posi- 2.2. Cell culture and plasmalogen precursor administration tion of the glycerol moiety brings the aliphatic chains closer together in comparison to their diacyl counterparts [23,24]. This leads to more Lymphoblast cell lines were established by Epstein–Barr virus fl packed membranes with decreased uidity and increased order, while transformation of the leukocytes isolated from the whole blood of two more easily promoting the formation of non-bilayer phases. In addition, BTHS patients and their gender- and age-matched control subjects using the vinyl-ether bond is oxidation-labile rendering plasmalogens the Ficoll–Hypaque gradients as previously described [11]. BTHS and ability to scavenger ROS, which led to the proposition they could act as control lymphoblasts were cultured in RPMI 1640 medium in the pre- a protection against the oxidation of polyunsaturated fatty acids sence of 10% FBS, penicillin (50 IU/mL), and streptomycin (50 μg/mL) (PUFAs) and other oxidation prone lipids [25–27]. Moreover, plasma- at 37 °C in a humidified 5% CO2 atmosphere. Cells were seeded at a logens are believed to act as reservoirs of second messengers as they density of ca. 2×105 cells/mL and passaged every 2–3 d. Adminis- are, usually, enriched with PUFAs at the sn-2 position of the glycerol tration of plasmalogen precursors was conducted by adding 30 μMof moiety, which are biologically active lipid mediators released upon HG and 5 μM of ethanolamine (this component was added to avoid it plasmalogen hydrolyses by PLA2 [22]. becoming rate limiting for the synthesis of PE-Pls) 20 h before har- A decrease in the steady-state levels of plasmalogens is associated vesting the cells [30]. Other two concentrations (2.5 fold above and with an impaired biosynthesis or an enhanced degradation. Currently below the one mentioned) of HG and ethanolamine were tested, but the mechanism of plasmalogen depletion in BTHS at the molecular level data is only presented for the above concentrations as they yielded the is not known. However, in several diseases
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